DESCRIPTION: (Applicant's Abstract) Cocaine addiction continues as one of our most costly social and medical problems. Neurobiological research into the mechanisms of cocaine addiction has focused primarily on the mesoaccumbens dopamine (DA) system. Yet, we have known for 15 years that the prefrontal cortex (PFC) is the site where cocaine self-administration is initiated. And, new evidence indicates that glutamatergic pyramidal neurons of the PFC are also necessary for the induction of cocaine sensitization and its cellular correlates. Surprisingly, we know almost nothing about how cocaine alters PFC neurons; indeed, we know very little about how DA modulates the neurophysiological properties of PFC pyramidal cells. This proposal describes a series of projects that are designed to fill these gaps in our knowledge with the long-term objective of identifying the cellular mechanisms responsible for cocaine sensitization and cue-elicited cocaine craving during withdrawal. More specifically, our specific goal is to identify the ion currents modulated by different DA receptor subtypes in PFC pyramidal neurons and to do so at precise sub-cellular components of these cells. More importantly, experiments are proposed to then determine how repeated cocaine self-administration alters these conductances and their modulation by specific DA receptors. In Aim 1, we will use whole cell voltage-clamp recordings from acutely dissociated PFC neurons to identify which DA receptors modulate which specific voltage gated Na+, Ca2+, and K+ currents. Biophysical and pharmacological procedures will be used to isolate specific currents. Selective agonists and antagonists for D1 and D2 class DA receptors will be used to identify these receptors, and receptor knockout mice (Dl, D2, D4, D5) will be used to distinguish receptors within each of these classes. In Aim 2, we will use dual somatic and dendritic whole-cell and cell-attached patch clamp methods in slices of PFC to identify potential differences in Na+ and K+ conductances, and their modulation by DA, within specific microdomains the neurons. In addition, we will determine whether DA receptors modulate action potential backpropagation as a means of selecting specific dendritic synapses for use-dependent plasticity. Once we have identified the effects of DA on specific conductances, we will compare rats that have self-administered cocaine to controls with respect to the state of each conductance and its responsiveness to DA receptor stimulation. We believe that these projects will isolate critical elements of cocaine addiction at a cellular level and that, as this work progresses, we may identify means by which cocaine addiction leads to maladaptive responses in susceptible individuals.